Inhibitor binding to topoisomerase II leading to infant leukaemia

This Adverse Outcome Pathway (AOP) describes the linkages between the perturbation of the normal topoisomerase II enzyme function and infant leukaemia. Infant leukaemia is a rare haematological disease (1 in 106 newborns, accounting for 10% of all childhood acute lymphoblastic leukaemias) of developmental origin, manifesting soon after birth (< 1 year old). The present AOP describes how interference of stressors with DNA topoisomerase II enzyme can possibly result in DNA double-strand break and chromosomal rearrangement during intrauterine development and lead to infant leukaemia, manifesting soon after birth. The proposed AOP is supported by a number of evidences by means of using etoposide as a model compound to empirically support the linkage between the proposed molecular initiating event and the adverse outcome. This AOP also identifies several knowledge gaps, the main ones being the identification of the initiating cell and the investigation of TopoII poisons in a robust model; thus, the present AOP may be modified in future on the basis of new evidence. This AOP is referred to as AOP 202 in the Collaborative Adverse Outcome Pathway Wiki (AOP-Wiki).